Disruptive visions: a robot is not a machine... systems integration for surgeons

The discipline of surgery has become even more complex with the rapid introduction of revolutionary technologies. Laparoscopic surgery is just the simplest and first of these new directions. Robotic surgery and image-guided therapy are the next generation. As biosurgery and other modalities are introduced, the complexity will increase exponentially. In order to understand and utilize the new technologies, surgeons need to be grounded in the science of systems integration. The pervasive influence of this new requirement, as well as the skills, education, training, and assessment needs, are defined. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official, or as reflecting the views of the Department of the Army, Department of the Navy, the Defense Advanced Research Projects Agency (DARPA), or the Department of Defense.     

Patient-controlled drug delivery for acute postoperative pain management: a review of current and emerging technologies

Postoperative pain management has dramatically improved with the advent of patient-controlled analgesia (PCA) delivery. The optimal PCA system would encompass several key characteristics, including consistent efficacy across a number of surgeries; safety of both the analgesic drug delivered and the delivery system; ease of setup, maintenance, and administration; patient comfort during analgesic delivery; avoidance of analgesic gaps; minimal invasiveness; and it would be associated with high patient satisfaction. Existing PCA modalities (using intravenous or epidural routes) encompass some of these characteristics (e.g., they have demonstrated efficacy across a number of surgeries); however, they are limited by the need for an indwelling catheter and the time and resources required for system setup and use. Device programming-related medication errors by hospital staff are an unfortunate risk, and could lead to significant harm. New PCA technologies are on the horizon that address some of the limitations to existing modalities; however, the added complexity of these newer systems are a concern, and their benefits and drawbacks remain to be assessed. These technologies include "smart" intravenous PCA infusion pumps to improve the safety of analgesic administration; needle-free options, such as the fentanyl HCl iontophoretic transdermal system for transdermal delivery; and a number of PCA devices for intranasal delivery, as well as several new options for patient-controlled regional analgesia. This review will discuss the benefits and drawbacks of both existing and emerging PCA modalities in the context of the ideal PCA system, and provide a critical evaluation of their use in postoperative settings.     

BPH in the next millennium:a glimpse to the future

Benign prostatic hyperplasia (BPH) is a highly prevalent, age-related disease. As the world population continues to grow and life expectancy increases, the population of men suffering from BPH will expand. A greater emphasis will be placed on quality of life. The BPH patient of the future will also have greater expectations regarding therapy, which will need to be effective in a shorter period of time. New technologies for the treatment of BPH are anticipated. Already, robot-operated vaporisation of the prostate is being undertaken. With regard to medical therapy, more selective and hence, more effective drugs are under development. With the identification of new alpha(1)-adrenoceptor subtypes, alpha-blocker therapy should target the prostate more accurately. Gene-based therapies will have an important role in the future. It is envisaged that technology will exist whereby defective genes can be replaced and gene expression controlled to overcome the disease process. Through pharmacogenomics, drugs will be tail-ored to the individual, which will, in turn, result in more economical use of medical therapy. Similarly, the development of nanotechnology will allow site-specific delivery of drugs. Together, these advances will make the treatment of BPH even more effective in the new millennium.     

Predicting and preventing cardiotoxicity in the era of breast cancer targeted therapies. Novel molecular tools for clinical issues

Treatment of breast cancer (BC) has changed over the last decade with the advent of targeted therapies. Whereas traditional chemotherapy was directed toward all rapidly dividing cells (cancerous or not), several new anti-cancer drugs are mainly tailored to specific genetic pathways of cancer cells.Ideally, the goal of these new therapies is to improve the management of cancer with a specific targeting of the malignant cell and fewer side effects than traditional chemotherapy. Due to the initial success of this approach, an increasing number of targeted drugs entered into clinical development. However, unanticipated side effects of the new drugs, such as cardiotoxicity and heart failure, emerged from several clinical trials. The mechanisms of cardiotoxicity due to traditional chemotherapy and the one due to new drugs seem to be inherently different. In the case of BC, available targeted therapies are probably associated with the abrogation of normal molecular pathways involved in cardiomyocytes and endothelial cells survival/proliferation. The cardiac safety profile of these new drugs asks for a careful patient monitoring and follow up.Herein we will review the cardiotoxicity of BC patients receiving antiERBB2 treatment (Trastuzumab, Lapatinib), VEGF inhibitors (Bevacizumab) and tirosin-kinase inhibitors (Sorafenib, Sunitinib). We will discuss the molecular mechanisms that underlie the risk of cardiotoxicity, and we will examine the molecular tools useful for prediction of heart failure and for identification of subgroups of BC patients more susceptible to cardiac side effects induced by targeted therapies. Attention will be paid in particular to ERBB2 gene and its polymorphisms, as well as to the possible genetic risk stratification of BC patients.Finally, we will discuss the possible clinical strategies to prevent and minimizing the cardiotoxicity of targeted therapies in BC patients, focusing in particular on new drugs combination and on the emerging role of a tight partnership between cardiologists and oncologists.     

Virtual reality surgical simulator

Summary The virtual-reality surgical simulator signals the beginning of an era of computer simulation for surgery. The surgical resident of the future will learn new perspectives on surgical anatomy and repeatedly practice surgical procedures until they are perfect before performing surgery on patients. Primitive though these initial steps are, they represent the foundation for an educational base that will be as important to surgery as the flight simulator is to aviation. It is anticipated that the full development of the surgical simulator will take less than the 40 years which was required for flight simulators to become an indispensable ingredient of pilot training. As the system evolves, many new and yet-to-be-imagined applications will arise, but we must have understanding and patience as we wait for computer power to improve to a point where VR surgical simulation can emerge from its PacMan era.The opinions or assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the Department of the Army or the Department of Defense     

New developments in cancer pain therapy

This review will summarize some of the potentially useful new drugs and therapies, which have already been applied in clinical practice or will potentially become available for cancer pain management in the near future. Included will be an introduction to drugs, which effectively relieve the breakthrough pain, a group of new sustained release long-acting opioids, Cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drug (NSAIDs), alpha-2 agonists, ion channel blockers, N-methyl-D-aspartate (NMDA) receptor antagonists, and new delivery systems.     

Current therapy for medulloblastoma

Opinion statement In the past three decades, the survival for patients with medulloblastoma has improved remarkably. Contemporary “standard” therapy for children with medulloblastoma consists of maximal surgical resection followed by craniospinal irradiation with a boost to the posterior fossa, combined with adjuvant chemotherapy. The use of such multimodal therapeutic approaches results in progression-free survival (PFS) rates of 75% to 80% for patients with average-risk disease and approximately 60% for highrisk patients. However, despite the marked improvements in survival, many therapeutic challenges remain. Children with macroscopic metastatic disease (M2/M3) at presentation continue to fare poorly, with the best reports only attaining PFS rates up to 40%. Furthermore, despite intensive multimodal therapy, some patients have disease progression or recurrence, which for most remains incurable. The early recognition of these patients is imperative in order to institute treatment modifications, such as intensification and/or the use of novel experimental therapies. Additionally, the price for cure is clearly evident in survivors, who suffer from significant, often debilitating long-term neurocognitive and neuroendocrine sequela. Using the current clinical stratification system, a significant number of patients are overtreated and unnecessarily subjected to these long-term toxicities. This group of patients would benefit from reductions in therapy. Refinements in patient stratification and further improvement in outcome are unlikely to be achieved without improved knowledge of tumor biology. Several molecular alterations have already been identified, many of which appear to have prognostic significance. Furthermore, the disruption of molecular alterations in signaling pathways involved in the development and maintenance of medulloblastoma using novel molecularly targeted therapies promises to improve outcomes and reduce toxicity for patients with medulloblastoma. It is envisaged that in the near future children diagnosed with medulloblastoma will be more accurately stratified based on a combination of clinical variables and molecular profiles. Improved risk stratification will permit delivery of individualized therapy using conventional treatment modalities in conjunction with novel targeted therapeutic approaches.     

Endoscopic therapy for chronic pancreatitis

Endoscopic therapy for chronic pancreatitis is feasible and effective in selected patients. The management of pain and ductal obstruction is most effective if reversal of the obstructive process--stricture or stone--is successful and durable. Multiple endoscopic modalities are available, and new technologies will continue to advance the capabilities of therapeutic pancreatic endoscopists. Adjunctive treatments, such as ESWL, enhance the success of these techniques. These varied therapies, although attractive and theoretically sensible, have not been compared in a randomized, controlled fashion with standard surgical therapies. In this sense, they remain experimental. Nonetheless, these techniques are widely applied in advanced endoscopy centers worldwide, and uncontrolled individual series are expected to continue to expound on and demonstrate the effectiveness of these minimally invasive interventions until randomized, prospective studies become available.     

Bioartificial kidney for full renal replacement therapy

The rapid understanding of the cellular and molecular basis of organ function and disease processes will be translated in the next millennium into new therapeutic approaches to a wide range of clinical disorders, including acute and chronic renal failure. Central to these new therapies are the developing fields of gene therapy, cell therapy, and tissue engineering. These new technologies are based on the ability to expand stem or progenitor cells in tissue culture to perform differentiated tasks and to introduce these cells into the patient either in extracorporeal circuits or as implantable constructs. Cell therapy devices are currently being developed to replace the filtrative, metabolic, and endocrinologic functions of the kidney lost in both acute and chronic renal failure. This article summarizes the current state of device development for a renal tubule assist device, a bioartificial hemofilter, and a regulatable erythropoietin cell therapy device. These individual devices have the promise to be combined to produce a wearable or implantable bioartificial kidney for full renal replacement therapy. These new approaches may result in therapeutic modalities that significantly diminish the morbidity and mortality in patients with acute renal failure or end-stage renal disease.     

Global burden of trauma: Need for effective fracture therapies

Orthopedic trauma care and fracture management have advanced significantly over the last 50 years. New developments in the biology and biomechanics of the musculoskeletal system, fixation devices, and soft tissue management have greatly influenced our ability to care for musculoskeletal injuries. Many therapies and treatment modalities have the potential to transform future orthopedic treatment by decreasing invasive procedures and providing shorter healing times. Promising results in experimental models have led to an increase in clinical application of these therapies in human subjects. However, for many modalities, precise clinical indications, timing, dosage, and mode of action still need to be clearly defined. In order to further develop fracture management strategies, predict outcomes and improve clinical application of newer technologies, further research studies are needed. Together with evolving new therapies, the strategies to improve fracture care should focus on cost effectiveness. This is a great opportunity for the global orthopedic community, in association with other stakeholders, to address the many barriers to the delivery of safe, timely, and effective care for patients with musculoskeletal injuries in developing countries.     

Conservative Treatment of the Uremic Syndrome

In addition to extracorporeal renal replacement strategies, which in chronic kidney disease (CKD) are largely reserved for the treatment of end-stage kidney failure, conservative measures can be taken to reduce concentration, effects, or both concentration and effects of uremic retention solutes. In this overview, we will focus on those therapies, which are aimed at preventing or delaying cardio-vascular disease, retarding or halting the progression of CKD, or both. We will discuss, consecutively, inhibitors of the renin–angiotensin–aldosterone axis, beta-blockers, calcium-channel antagonists, anti-inflammatory drugs, intestinal sorbents, calcimimetics, and glitazones. Some of these approaches could lead to a therapeutic breakthrough in the future. In addition, comprehensive tables will be provided for more traditional therapeutic approaches, such as lifestyle changes and other pharmaceutical treatments.     

Minimally invasive therapies for prostatitis

A plethora of reports describe a number of promising new minimally invasive treatment modalities available to patients with chronic prostatitis. This article reviews these studies, with most evaluating treatments using heat or intraprostatic injection. The results are difficult to compare because of the inconsistencies in study design, modalities of treatment, and outcome measures. Standard criteria for assessing symptom severity in chronic prostatitis recently have been developed and prospective clinical trials are underway to evaluate minimally invasive therapies for this debilitating condition. Until definitive data from these trials are available, minimally invasive therapies most likely will continue to be empirical and not a standard of care.     

Neurodegeneration: An early event of diabetic retinopathy

Diabetic retinopathy (DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia. However, retinal neurodegeneration is already present before any microcirculatory abnormalities can be detected in ophthalmoscopic examination. In other words, retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR. Therefore, the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR. Elevated levels of glutamate and the overexpression of the renin- angiotensin-system play an essential role in the neurodegenerative process that occurs in diabetic retina. Among neuroprotective factors, pigment epithelial derived factor, somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review. Nevertheless, it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neurotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye. New strategies, based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors, are currently being tested in experimental models and in clinical pilot studies. Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research.     

New therapies and delivery mechanisms for treatment of erectile dysfunction

Despite the successes of Viagra, the quest for new and better therapy for erectile dysfunction (ED) continues. In a recent survey of the first 220 patients placed on Viagra at our institution, 101 (46%) quit taking the drug: 76% of those who quit were not satisfied with the results. Patients clearly want an efficacious, safe, convenient medication with rapid onset. To meet these consumer demands, numerous new therapies are being developed. These include new oral medications, new intracavernosal pharmacotherapies, new delivery systems (such as novel intracorporal injectors and transdermal agents) and combination therapies. What is known about these new medications and delivery systems will be presented. Hopefully, from these innovations will come therapies that will improve the overall success and acceptance of treatment for ED. Since it is unlikely that any single agent will ever provide a solution for all men with ED, an expanded armamentarium of treatment options will greatly enhance the chances that any given man will be able to find a therapy that is both acceptable and appropriate to him. International Journal of Impotence Research (2000) 12, Suppl 4, S158-S162.     

Genome analysis and cancer therapy

Application of the human genome information would lead to the development of novel diagnostic methods and innovative therapies against cancer. In this article, two aspects of such application are reviewed; 1) genomic diagnosis for predicting efficacy and side effects associated with the administration of the anti-cancer drugs, 2) exploration of novel cancer associated gene products using genome-wide gene-expression profiling. Successful examination on genetic information of the patients/tumors would lead to the establishment of the "personalized" medicine which could be an ideal situation for the cancer patients treated with the chemotherapeutic drugs. Furthermore, the finding of tumor associated antigens lead to the development of not only new diagnostic methods but also novel therapeutic modalities including cancer vaccine. Some of the successful efforts are referred and discussed.     

Long-lived autoreactive plasma cells drive persistent autoimmune inflammation

Aberrant production of autoantibodies by inappropriately self-reactive plasma cells is an inherent characteristic of autoimmune diseases. Several therapeutic strategies aim to deplete the plasma cell pool, or to prevent maturation of B cells into plasma cells. However, accepted views of B-cell biology are changing; recent findings show that long-lived plasma cells refractory to immunosuppressants and B-cell depletion therapies contribute to the maintenance of humoral memory and, in autoimmunity, to autoreactive memory. As a consequence of their longevity and persistence, long-lived plasma cells can support chronic inflammatory processes in autoimmune diseases by continuously secreting pathogenic antibodies, and they can contribute to flares of symptoms. As long-lived plasma cells are not sufficiently eliminated by current therapies, these findings are extremely relevant to the development of novel concepts for the treatment of autoimmune diseases. Thus, long-lived plasma cells appear to be a promising new therapeutic target.     

New drugs and new approaches for the treatment of metastatic urothelial cancer

The median survival of patients with metastatic bladder cancer treated with M-VAC is approximately 1 year and long-term survival occurs in a small proportion of patients. Recent efforts to improve the outcome of patients with metastatic transitional cell carcinoma have focused on identifying new drugs with single agent activity and on their incorporation into platinum-based combination regimens. Paclitaxel, docetaxel, ifosfamide and gemcitabine are among the most active new agents. A large number of phase I-II trials have evaluated these agents in two- and three-drug combination regimens. The response proportion observed with these combinations varies considerably and median survival times range from 8 to 20 months. A better understanding of the molecular biology of bladder cancer will undoubtedly influence the selection of new therapeutic modalities. Molecular targeted small molecule therapy and monoclonal antibodies have begun to dominate contemporary studies. Whether or not this approach to therapy will lead to better results must still be determined.     

Renal Transplantation Across HLA and ABO Antibody Barriers: Integrating Paired Donation into Desensitization Protocols

The field of desensitization and incompatible transplantation has made great gains over the past decade. There are now several options and effective therapies for many patients who face antibody barriers. Kidney paired donation (KPD) and desensitization have traditionally been considered competing strategies and patients have been offered one or the other without regard for the probability of a successful outcome. It is now possible to predict which donor/recipient phenotypes will benefit from each of these modalities. KPD should be favored among patients with immunologic phenotypes that are likely to match without prolonged waiting times. However, as many as 50% of patients with incompatible donors will fail to find a match in a KPD pool and many of these patients could be desensitized to their donor. Positive crossmatch and ABO incompatible transplantation has been accomplished in selective cases without the need for heavy immunosuppression or B‐cell ablative therapy. Patients who are both difficult‐to‐match due to broad sensitization and hard‐to‐desensitize because of strong donor reactivity can often be successfully transplanted through a combination of desensitization and KPD. Using these various modalities it is estimated that most patients with incompatible live donors can undergo successful renal transplantation.